The transforming growth factor β (TGF-β) family of proteins includes the transforming growth factors-β (TGF-β), activins, bone morphogenic proteins (BMP), nerve growth factors (NGFs), brain-derived neurotrophic factor (BDNF), and growth/differentiation factors (GDFs). These family members are involved in the regulation of a wide range of biological processes including cell proliferation, differentiation, and other functions. Activins were originally discovered as gonadal peptides involved in the regulation of follicle stimulating hormone synthesis, and are now believed to be involved in the regulation of a number of biological activities including control of section and expression of anterior pituitary hormones such as FSH, GH, and ACTH, neuron survival, hypothalamic oxytocin secretion, erythropoiesis, placental and gonadal steroidogenesis, early embryonic development, and proliferation of some types of tumors. Activins A, B and AB are the homodimers and heterdimer respectively of two polypeptide chains, βA and βB (Vale et al. Nature 321, 776-779 (1986), Ling et al., Nature 321, 779-782 (1986)). These two β chains can also dimerize with a related a chain giving rise to inhibins A and B respectively (Mason et al, Nature 318, 659-663 (1986)). It is well established that inhibins are necessary for maintaining normal function in many tissues, particularly those associated with reproductive functions. In these tissues inhibins oppose many, but not all, of the activin activities.
Growth/differentiation factor 8 (GDF-8), also referred to as myostatin, is a TGF-β family member expressed for the most part in the cells of developing and adult skeletal muscle tissue. Myostatin appears to play an essential role in negatively controlling skeletal muscle growth (McPherron et al. Nature (London) 387, 83-90 (1997)). Antagonizing myostatin has been shown to increase lean muscle mass in animals (McFerron et al, supra, Zimmers et al, Science 296:1486 (2002)).
Another member of the TGF-β family of proteins is a related growth/differentiation factor, GDF-11. GDF-11 has approximately 90% identity of the amino acid sequence of myostatin. GDF-11 has a role in the axial patterning in developing animals (Oh et al, Genes Dev 11:1812-26 (1997)), and also appears to play a role in skeletal muscle development and growth. However, the postnatal role of GDF-11 is not currently understood.
A family of transmembrane serine/threonine kinases are known to act as receptors for activins and other TGF-β family members. These receptors fall into two distinct subfamilies known as type I and type II receptors that act cooperatively to bind ligand and transduce signal (Attisano et al., Mol Cell Biol 16 (3), 1066-1073 (1996)). Most TGF-β ligands are believed bind first to a type II receptor and this ligand/type II receptor complex then recruits a type I receptor (Mathews, L S, Endocr Rev 15:310-325 (1994); Massague, Nature Rev: Mol Cell Biol. 1, 169-178 (2000)). The type II receptor kinase then phosphorylates and activates the type I receptor kinase, which in turn phosphorylates the Smad proteins. Activins initially bind their type II receptors ActRIIA for activin A, or ActRIIB for activin B. This is followed by the recruitment, phosphorylation and subsequent activation of the type I receptor, activin-like kinase 4 (ALK4). On activation, ALK4 binds and then phosphorylates a subset of cytoplasmic Smad proteins (Smad2 and Smad3) that produce signal transduction for activins (Derynck, R et al. Cell 95, 737-740 (1998)).
Cross-linking studies have determined that myostatin is capable of binding the activin type II receptors ActRIIA and ActRIIB in vitro (Lee et al. PNAS USA 98:9306-11 (2001)). There is also evidence that GDF-11 binds to both ActRIIA and ActRIIB (Oh et al., Genes Dev 16:2749-54 (2002)).
TGF-β proteins are known to be associated with a variety of disease states and antagonizing these proteins may be useful as therapeutic treatments for the disease states. In particular antagonizing several TGF-β proteins simultaneously may be particularly effective for treating certain diseases. The present invention provides a novel composition of matter and methods of using the composition of matter as a treatment for muscle-related and other disorders.